L-METHIONINE

BACKGROUND

Ingredient Type: Amino Acid

Also Known As: DL-Methionine, DL-Méthionine, L-2-amino-4-(methylthio) butyric acid, L-Methionine, L-Méthionine, Méthionine, Metionina, L-alpha-Amino-gamma-methylmercaptobutyric acid, (S)-2-Amino-4-(methylthio)butanoic acid,

L-methionine, or methionine, is a sulfur containing essential amino acid that is found in food as well as in a supplemental form. It is considered one of the main building blocks for proteins in the body and is necessary for the growth and repair of tissues, as well as for numerous metabolic and detoxification processes. The two forms of methionine are L-methionine, which is the naturally occurring form, and D-methionine. The mixture of both forms is called DL-methionine. From a dietary standpoint, methionine is commonly found in dairy products, fish, meats, whole grains, and nuts.

Methionine was originally discovered in the 1920’s by a Columbia University researcher by the name of J.H. Muller. While he is noted to have discovered the amino acid, a fellow researcher by the name of Odake, from Japan, re-submitted a correct summation formula for methionine (9). Upon Muller’s discover, it was said that the methionine was initially isolated from casein, which is a family of related phosphoproteins that are commonly found in milk. Its importance can be found in the methylation processes as well as a precursor for the two amino acids, cystine and cysteine (9).

TRADITIONAL USES

Prior to the use for medicinal and nutraceutical purposes, the DL-methionine form had been primarily manufactured following WWII in order to alleviate the protein shortage in Germany postwar. Shortly thereafter, the use of methionine shifted and was utilized to fortify animal-feed. Today, methionine is considered one of the key elements in modern animal nutrition (11).

Since this time, especially with further research and understanding, the uses of methionine have expanded dramatically. From adding to wound healing to helping those with such conditions as Parkinson’s, colorectal cancer, and various mental disorders. While methionine is commonly found in many foods that we consume on a daily basis, those who are on particular diets that minimize animal derived products should ensure appropriate supplementation of methionine through the consumption of nuts and grains.

WHAT DOES SCIENCE TELL US?

L-Methionine and Acetaminophen Overdose:

Statistically speaking, in the U.K., Paracetamol, a.k.a. acetaminophen, directly causes around 150 deaths per year. The researchers of this study conducted a systematic review to identify what treatment options are available for acute paracetamol poisoning. The databases reviewed for this research were: Embase, The Cochrane Library, Medline, as well as other major databases. A total of 127 studies were screened in the review, with 18 qualified after removal of duplicative articles and conference abstracts. Of the studies reviewed, there were a total of six interventions categorized based on effectiveness and safety. The following interventions included: acetylcysteine, activated charcoal, gastric lavage, hemodialysis, liver transplant, and methionine. According to the studies, methionine was noted to possibly reduce the risk of hepatic damage and mortality following paracetamol poisoning when compared with just supportive care. Further research and analysis however are required to support this finding (13).

This study was conducted to observe the effectiveness of oral methionine against paracetamol (acetaminophen) poisoning. There was a total of 132 cases of severe paracetamol poisoning that were treated with methionine. Seven of the 96 patients who received the treatment within ten hours of overdose ingestion presented with severe liver damage. 36 patients who received the treatment between 10 – 24 hours of ingestion presented with severe liver damage in 47% of the patients; 2 patients died. According to the researchers, the noted side effects in this study were considered insignificant. Based on the observations, it was concluded that oral methionine when administered within ten hours of ingestion is as effective as acetylcysteine in the prevention of severe liver damage and or death following paracetamol poisoning (17).

Another similar study had been conducted to assess the activity of orally introduced methionine against potential hepatic damage due to elevated levels of paracetamol ingestion. In this study, 30 patients who were considered at risk for hepatic damage were given 2.5g of oral methionine 4 times per day within the first ten hours of overdosing on paracetamol. Based on the results observed from all 30 patients, there was no reported mortality, hepatic encephalopathy, or other related complications. Of the 30 patients, 21 of the patient’s plasma aspartate-aminotransferase levels remained within normal limits, indicating normal hepatic function. The researchers concluded that methionine may be an effective alternative at reducing the severity and occurrence of hepatic damage due to paracetamol toxicity (2).

L-Methionine and Colon Cancer:

B vitamins have long been studied in their function regarding DNA repair, replication, and gene expression. Current studies have been focusing on the role of B vitamins and certain cancers. There however has been little research on the effects of methionine on colorectal cancer. This study observed these associations in 14,645 men and 22,467 women over a 15-year period. Of the total population assessed, 910 incidents of colorectal cancer were observed. From the data compiled, the researchers observed a u-shaped relationship between the risk of colon cancer and the intake of B6, along with an inverse relationship between the risk of rectal cancer and B12. According to the researchers, it is suggested that adequate folate intake may support the protection of colon cancer in those with low methionine intake (1).

This meta-analysis of prospective studies was conducted in order to investigate the relationship between dietary methionine intake and the risk of colon cancer incidence as epidemiologic findings are inconsistent when it comes to the correlation. The databases utilized in this study were PubMed and Embase. Of the 431, 029 participants reviewed, 6,331 had incidence of colorectal cancer. Based on analyses of the random-effects model and relative risks associated with methionine intake, a significant inverse association was observed between methionine intake and the risk of colorectal cancer incidence. It was concluded through the analysis of the data that dietary intake of methionine may be associated with a decreased risk of colorectal cancer, although further research is necessary to support these findings (18).

As it is known that cancer has a significant metabolic component, scientists are researching whether nutrition and other dietary interventions could lead to beneficial therapeutic outcomes. In this study, it is revealed that the dietary restriction the essential amino acid, methionine, has an influence on cancer outcome. In a controlled feeding study, both in the human model as well as the mouse mode, it was observed that methionine restriction resulted in systemic metabolic activity that positively indicated that dietary manipulation has the ability to directly affect tumor cell metabolism thus, an ability to mediate aspects of cancer outcomes (3).

L-Methionine and the Immune System:

The immune system is a very complex and highly integrated system that involves various feedback systems. Another key component of a proper functioning immune system are the raw materials involved in the processes for activation, maintenance, and surveillance; more specifically the components derived from dietary intake. This study was conducted in order to assess a diet-induced non-alcoholic fatty liver disease due to deficiencies in methionine and choline. The researchers sought to identify how supplementation with l-methionine and S-adenosylmethionine could aid in immune modulation. It was concluded that methionine is vital in the metabolic pathways associated with immune function (15).

Methionine, a limiting amino acid, is one of the key components in immune system function. Researchers conducted this study in order to review the effects of both methionine-deficient and methionine-supplemented diets on immune function. Subjects in the deficient group were fed a diet that met the daily amino-acid requirements, except for methionine. The subjects in the supplemented group were fed a diet that met the daily amino-acid requirements, including for methionine. The researchers observed methionine expression and immune-enhancement following 2 weeks and 12 weeks of feeding, more so following 12-weeks. The researcher concluded that methionine is not only an important factor for general metabolic needs but for immune function as well (8).

This particular study assessed the activity of dietary supplementation with either free methionine or methionine dipeptide on immune gene expression, antioxidant function, as well as amino acid transport in the jejunum in broiler chickens. Following testing and review of the measurable data (feed conversion ratio, weight of intestine and spleen, antioxidant capacity levels and immune metabolic activity), the results indicated supplementation with methionine, either as a free form or dipeptide, has intestinal protective effects against oxidative damage induced by free radicals (4).

L-Methionine Restriction

Whether related to genetic predispositions or condition specific needs methionine, while necessary may require reduced or increased levels. One’s individual need will vary based on a few factors such as dietary intake, genetic mutations or disruptions in related metabolic pathways, any present illness and one’s current state of health. While we know methionine is considered an essential amino acid, which we must consume through dietary or supplemental forms, there can be much confusion regarding methionine restriction or supplementation. Due to this confusion, it is highly recommended to work with your healthcare provider to determine the best steps when thinking about increasing or decreasing your methionine intake, whether through the dietary or supplemental form.

Methionine restriction has been found to increase lifespan and decrease aging-related disease processes in animals. However, at this time little is known about how methionine restriction in humans affects the metabolic pathways involved in disease, lifespan, or aging. The few studies that have assessed lifespan and methionine have associated a methionine restriction with an extension in lifespan in the mouse model (6, 12). Regarding the aging process there have also been several studies conducted on mice that reflect the restriction of methionine, inhibiting certain aging-related diseases processes (5, 7, 14).

SAFETY

Although methionine has been on the market for some time in various forms, supporting different industries, little research has been conducted regarding its effectiveness beyond acetaminophen toxicity. However, generally, when consumed orally using prescribed dosages, under the guidance of a healthcare professional, methionine supplementation is considered fairly safe. Regarding taking methionine intravenously to treat acetaminophen poisoning under the supervision of a healthcare provider, it is considered possibly safe depending on the dosage and timeframe taken in both children and adults.

It is NOT recommended to treat oneself or self-medicate with methionine. Especially at high levels, methionine can be toxic to the brain, potentially resulting in death. Methionine has also been linked with increasing homocysteine levels, potentially yielding to heart disease and other more serious conditions such as the promotion of tumor growth (10).

SIDE EFFECTS

It is NOT recommended to treat oneself or self-medicate with methionine. Especially at high levels, methionine can be toxic to the brain, potentially resulting in death. Methionine has also been linked with increasing homocysteine levels, potentially yielding to heart (10).

Interactions (10)

Pregnancy & Breastfeeding: Unfortunately, there is not enough reliable evidence that points to the safety of taking methionine when pregnant or breastfeeding. It is recommended that a medical professional is consulted prior to supplementing with methionine.

Acidosis: Those who have been diagnosed with acidosis should avoid supplementation with methionine as it can caused changes in the acidity of the blood.

Arthrosclerosis: Methionine has been found to increase levels of homocysteine, especially in those who are deficient in folate, B12 or B6, as well as those who have trouble processing homocysteine. Elevated, chronic levels of homocysteine have been associated with higher risk of heart and blood vessel disease.

Cirrhosis: Methionine may potentially exacerbate the condition of the liver. There is not enough evidence to indicate otherwise.

MTHFR Deficiency: An inherited disorder, supplementing methionine with a MTHFR deficiency may lead to elevated levels of homocysteine which can increase one’s risk of heart and blood vessel disease. It is highly recommended that you consult your healthcare provider prior to consuming supplemental methionine to determine if your inherited mutation can support supplemental methionine of not.

Tumors: Some studies have suggested that methionine can promote the growth of some tumors. If you have are suspect to have malignant or benign tumors, it is highly recommended that your healthcare provider prior to consuming supplemental methionine.

Schizophrenia: Those diagnosed with schizophrenia may experience the following effects when supplementing with larger doses of methionine (20g/ day for 5+ days): confusion, disorientation, delirium, agitation, listlessness.

REFERENCES

1. Bassett, Julie K et al. “Dietary intake of B vitamins and methionine and colorectal cancer risk.” Nutrition and cancer 65,5 (2013): 659-67. doi:10.1080/01635581.2013.789114
2. Crome, G.N. Volans, J.A. Vale, B. Widdop, R. Goulding, “Oral Methionine in the Treatment of Severe Paracetamol (Acetaminophen) Overdose” the Lancet. (308) 7990; (1976) Pages 829-830. SSN 0140-6736. https://doi.org/10.1016/S0140-6736(76)91211-3.
3. Gao, X., Sanderson, S.M., Dai, Z. et al.Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401 (2019). https://doi.org/10.1038/s41586-019-1437-3
4. Khatlab, Angélica de Souza et al. “Dietary supplementation with free methionine or methionine dipeptide mitigates intestinal oxidative stress induced by Eimeria challenge in broiler chickens.” Journal of animal science and biotechnologyvol. 10 58. 27 Jun. 2019, doi:10.1186/s40104-019-0353-6
5. Komninou, Despina et al. “Methionine restriction inhibits colon carcinogenesis.” Nutrition and cancer 54,2 (2006): 202-8. doi:10.1207/s15327914nc5402_6
6. Lee, Byung Cheon et al. “Methionine restriction and life-span control.” Annals of the New York Academy of Sciences 1363 (2016): 116-24. doi:10.1111/nyas.12973
7. Liou Sun, Amir A. Sadighi Akha, Richard A. Miller, James M. Harper, Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age, The Journals of Gerontology: Series A, Volume 64A, Issue 7, July 2009, Pages 711–722, https://doi.org/10.1093/gerona/glp051
8. Machado, M., Engrola, S., Colen, R., Conceicao, L., Dias, J., & Costas, B. (2020). Dietary methionine supplementation improves the European seabass Dicentrarchus labrax immune status following long-term feeding on fishmeal-free diets. British Journal of Nutrition, 124(9), 890-902. doi:10.1017/S0007114520001877
9. “Methionine: Chemical Compound.” The Editors of Encyclopedia Britannica. https://www.britannica.com/science/methionine
10. “Methionine.” RX-List. https://www.rxlist.com/methionine/supplements.htm
11. “Milestones of Chemistry Methionine.” Evonik Industries AG. Thomas Kaufmann. https://www.corporate.evonik.com/misc/micro/methionine/methionin_en.html
12. Miller, Richard A et al. “Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance.” Aging cell 4,3 (2005): 119-25. doi:10.1111/j.1474-9726.2005. 00152.x
13. Park BK, Dear JW, Antoine DJ. Paracetamol (acetaminophen) poisoning. BMJ Clin Evid. 2015; 2015:2101.
14. Richie, J P Jr et al. “Methionine restriction increases blood glutathione and longevity in F344 rats.” FASEB journal: official publication of the Federation of American Societies for Experimental Biology 8,15 (1994): 1302-7. doi:10.1096/fasebj.8.15.8001743
15. Singh Rawat, Bhupendra et al. “Methionine- and Choline-Deficient Diet Identifies an Essential Role for DNA Methylation in Plasmacytoid Dendritic Cell Biology.” Journal of immunology (Baltimore, Md.: 1950) 208,4 (2022): 881-897. doi:10.4049/jimmunol.2100763
16. Stern LL, Bagley PJ, Rosenberg IH, Selhub J. Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene. J Nutr. 2000 Sept; 130(9):2238-42. PMID:10958818 DOI: 1093/jn/130.9.2238
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18. Zhou, Z-Y et al. “Dietary Methionine Intake and Risk of Incident Colorectal Cancer: A Meta-Analysis of 8 Prospective Studies Involving 431,029 Participants.” PLoS ONE. 2013 Dec. 8(12): e83588. https://doi:10.1371/journal.pone.0083588